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Amine degradation in CO2 capture. 2. New

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International Journal of Greenhouse Gas Control 19 (2013) 576583

Contents lists available at ScienceDirect

International Journal of Greenhouse Gas Control

journal homepage: www.elsevier.com/locate/ijggc

Amine degradation in CO2 capture. 2. New degradation products of

MEA. Pyrazine and alkylpyrazines: Analysis, mechanism of formation
and toxicity
A. Rey a , C. Gouedard b , N. Ledirac c , M. Cohen a , J. Dugay a , J. Vial a , V. Pichon a ,
L. Bertomeu c , D. Picq b,d , D. Bontemps e , F. Chopin e , P.-L. Carrette b,
a

LSABM, UMR PECSA 7195, ESPCI UPMC CNRS, 10 rue Vauquelin, 75005 Paris, France
IFP Energies nouvelles, Rond-point de lchangeur de Solaize, BP 3, 69360 Solaize, France
c
CEHTRA, 43 rue Laroque, 33560 Sainte Eulalie, France
d
LEPMI, UMR 5279, CNRS Grenoble INP Universit J. Fourier, 1130 rue de la Piscine, BP 75, 38402 Saint Martin dHres, France
e
EDF R&D, 6, quai Watier, 78401 Chatou Cedex, France
b

a r t i c l e

i n f o

Article history:
Received 13 June 2013
Received in revised form 11 October 2013
Accepted 15 October 2013
Keywords:
Post-combustion CO2 capture
MEA degradation
Pyrazines toxicity
HS-SPME coupled with GCMS
Mechanisms
SAR

a b s t r a c t
Amine degradation in post-combustion CO2 capture is a main problem because of its consequences on
process units and the potential impact of degradation products on environment. Ethanolamine (MEA) is
the benchmark amine for this application. Although MEA degradation has been intensively studied, some
degradation products are still unidentied. In this article, new degradation products of MEA are reported:
pyrazine and 9 alkylpyrazines. A new analytical method based on HS-SPME and GCMS was developed
to identify and quantify the 10 pyrazines present in two pilot plant samples. A mechanism for their
formation was proposed. The toxicity of these molecules was assessed based on available toxicological
data and, when the information was not sufcient, a computational approach was used: TOPKAT and
DEREK SARs. LD50 , skin and eye irritancy potential, genotoxicity and reproductive effects were assessed.
The study showed that the ten identied pyrazines are currently not indicating toxicological concern at
the level of intake estimated at 0.2120 g/day in Europe.
2013 Elsevier Ltd. All rights reserved.

1. Introduction
CO2 capture and storage is one of the promising technologies
to reduce greenhouse gas emissions. To be used, this technology needs economic but also environmental acceptance. In this
process, amines are known to react with ue gas components
(O2 , CO2 , NOx, SOx. . .) to form degradation products, and some
of them could be potentially dangerous to humans or environment according to their toxicity and their concentration. These
products could be discharged to the atmosphere essentially with
treated ue gas. Such amine degradation causes also amine loss,
therefore additional costs, and can lead to corrosion (DeHart

Abbreviations: DEREK, deductive estimate of risk from existing knowledge;

FEMA, avor and extract manufacturers association; GRAS, generally recognized
as safe; HS, head space; MSDI, maximised survey-derived daily intakes; SAR,
structureactivity relationship; SIM, single ion monitoring; SPME, solid phase micro
extraction; TIC, total ion current; TOPKAT, toxicity prediction by komputer assisted
technology.
Corresponding author. Tel.: +33 437 70 27 23; fax: +33 437 70 20 66.
E-mail address: p-louis.carrette@ifpen.fr (P.-L. Carrette).
1750-5836/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijggc.2013.10.018

et al., 1999; Islam et al., 2011; Martin et al., 2012), solid deposit
(Chakma and Meisen, 1987) and foaming (Kohl and Riesenfeld,
1985).
Therefore it is necessary to list all the degradation products of
amines used in CO2 capture, to understand their formation and to
study their toxicity.
Alkanolamines are the most studied molecules regarding degradation in the case of CO2 capture and natural gas sweetening.
The benchmark molecule is monoethanolamine (MEA) (Davis
and Rochelle, 2009; Fostas et al., 2011; Lepaumier et al., 2011;
Sexton, 2008; Strazisar et al., 2003; Supap et al., 2011; Vevelstad
et al., 2011), but some other amines were studied: mainly
diethanolamine (DEA) (Chakma and Meisen, 1986; Choy and
Meisen, 1980; Holub et al., 1998), methyldiethanolamine (MDEA)
(Chakma and Meisen, 1988, 1997; Lawal et al., 2005), piperazine
(PZ) (Freeman et al., 2010; Freeman and Rochelle, 2011) and 2amino-2-methylpropan-1-ol (AMP) (Wang and Jens, 2012). Some
alkylamines and polyamines were studied too (Lepaumier et al.,
2009a,b, 2010). The identication of amine degradation products and their mechanisms of formation were recently reviewed
(Gouedard et al., 2012).

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

Although MEA is the most studied amine for CO2 capture, some
degradation products are still unidentied (da Silva et al., 2012).
In this article, ten new degradation products of MEA are
reported: pyrazine and nine alkylpyrazines. They were observed in
liquid samples of two pilot plants at IFP Energie nouvelles (IFPEN)
and EDF R&D, respectively. They were identied and quantied
thanks to the development of a new analytical method based on
HS-SPME and GCMS.
A mechanism of formation was proposed in accordance with
literature.
The toxicity of these molecules was assessed based on available
toxicological data and, when the information was not sufcient,
a computational (in silico) approach was used. Predictions were
generated by using two structureactivity relationship (SAR) software tools, one based on expert rules, DEREK (deductive estimate
of risk from existing knowledge) and another based on statistical
methodologies, TOPKAT (toxicity prediction by komputer assisted
technology). LD50 , skin and eye irritancy potential, genotoxicity and
reproductive effects were assessed.
2. Material and methods
2.1. Chemicals and SPME materials
Pyrazine, 2-methylpyrazine, 2,3-dimethylpyrazine, 2,5dimethylpyrazine, 2,6-dimethylpyrazine, 2-ethylpyrazine, 2,3,
5-trimethylpyrazine, 2-ethyl-3-methylpyrazine, a mix of isomers 2-ethyl-5-methylpyrazine and 2-ethyl-6-methylpyrazine
and ethanolamine (ReagentPlus , 99%) were purchased from
SigmaAldrich (Saint Quentin Fallavier, France). Ultra pure water
was produced using a Direct-Q UV 3 system (18.2 M/cm) from
Millipore (Molsheim, France). 75 m Carboxen/PDMS SPME
bre were obtained from Supelco (SigmaAldrich, Saint Quentin
Fallavier, France).
The liquid sample from IFPEN CO2 capture pilot plant was
obtained after 1000 h. The synthetic ue gas composition was CO2
14.9% N2 68.1% and O2 17%. Gas ow rate was 750 NL/h and liquid
ow rate was 2.5 L/h. Absorber temperature prole was 3658 C
and bottom stripper temperature was 108 C at atmospheric pressure. 40% weight MEA solution used for the pilot plant campaign
was provided by Carlo Erba.
The liquid sample from EDF R&D lab-scale pilot plant was
obtained after about 400 h (more details about the equipment will
be published soon). The synthetic ue gas composition was CO2
15% N2 82% and air 3%. Gas ow rate was 1800 NL/h and liquid ow
rate was 30 L/min. Absorber temperature was 50 C at atmospheric
pressure and stripper temperature was 120 C at 4 bara. 30% weight
MEA solution used for the pilot plant campaign was provided by
Alfa Aesar.
2.2. GCMS analysis
Analyses were performed on an Agilent 7890A gas chromatograph coupled with an Agilent 5975C inert XL MSD mass
spectrometer (Santa Clara, USA). The device is equipped with a MPS
autosampler from Gerstel (RIC, Saint-Priest, France) that enabled
fully automated HS-SPME analyses. Two columns were used to separate all the target compounds, a non-polar fused silica capillary
column CP-SIL 8CB-ms (30 m 0.25 mm with 1 m lm thickness)
and a polar fused silica capillary column DB-WAX (30 m 0.25 mm
with 0.5 m lm thickness), both columns were obtained from
Agilent. Two temperature gradients were used, one for each
column. For the non-polar column, initial temperature was 40 C
held for 2 min then raised to 130 C at 7 C/min, increased to 280 C
at 13 C/min and held for 10 min. For the polar column, oven

577

Table 1
Pyrazine and alkylpyrazines studied standards, with the selected ion for detection
in MS SIM mode and their retention times on both columns used.
Pyrazines

Pyrazine
2-methylpyrazine
2,5-dimethylpyrazine
2,6-dimethylpyrazine
2-ethylpyrazine
2,3-dimethylpyrazine
2-ethyl-6-methylpyrazine
2-ethyl-5-methylpyrazine
2,3,5-trimethylpyrazine
2-ethyl-3-methylpyrazine

MW (g/mol)

80
94
108
108
108
108
122
122
122
122

m/z

80
94
108
108
107
67
121
121
42
121

Ret. time (min)

Non-polar

Polar

9.28
11.86
14.27
14.29
14.44
14.47
16.38
16.51
16.47
16.50

12.38
13.55
14.72
14.84
14.95
15.22
15.92
16.06
16.27
16.30

temperature programme started at 40 C, held for 2 min then raised

to 130 C at 7 C/min, increased to 200 C at 10 C/min held for 7 min.
In both cases, helium was used as carrier gas in constant ow mode
at 1 mL/min. The transfer line temperature to the MS detector was
set at 280 C.
Mass spectrometer was used with the electronic ionization
source (70 eV) heated at 250 C. The acquisition was made with scan
and SIM mode simultaneously. The scan range was 25250 amu and
SIM parameters are shown in Table 1.
2.3. HS-SPME procedures
For HS-SPME procedures, standards were prepared by spiking a
solution of water/ethanolamine (70/30 v/v) to mimic a real solution
used for CO2 capture. The volume of sample introduced in the 20 mL
HS vial was 5 mL both for synthetic and real samples.
The fully automated HS-SPME procedure was as follows. First,
the vial was equilibrated at 70 C during 5 min then the Carboxen/PDMS bre was placed into the head-space of the sample
for the extraction, still maintained at 70 C for 30 min. At the end of
the extraction, the bre was desorbed directly in the injector set at
250 C in split mode (1:5).
2.4. Toxicity analysis (DEREK and TOPKAT)
Derek Nexus version 3.0.0 (LHASA Limited, Leeds, UK) and TOPKAT DS 3.5 (Accelrys Software Inc., Discovery Studio Modelling
Environment, Release 3.5, San Diego: Accelrys Software Inc., 2007)
were used in this study. The individual structure of each pyrazine
derivative was imported into both QSAR models and processed.
TOPKAT and DEREK were used to predict genotoxicity (AMES
prediction with TOPKAT, structural alerts for mutagenicity and
chromosome damage with DEREK), skin and eye irritation potential, and the sensitization effect of the molecules. TOPKAT was also
used for continuous measurements for quantiable endpoints such
as LD50 values.
2.5. TOPKAT criteria for positivity and negativity
TOPKAT conrms if the query structure is in the model applicability domain (i.e. in the Optimal Predictive Space OPS) which
indicates the level of condence in the prediction. This criterion was
checked and when the submitted structure was outside the OPS, the
prediction results were considered unreliable. Then, predictions
with a probability values greater than or equal to 0.7 were considered positive and below 0.3 were considered negative. Results
falling between 0.3 and 0.7 were considered equivocal (Snyder
et al., 2004). Additional parameters provided by TOPKAT were used
such as the enrichment, the Mahalanobis Distance or the Bayesian
score in order to support the reliability of TOPKAT predictions. All

578

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

statistical calculations were considered together to assess the condence in the prediction.
2.6. DEREK criteria for positivity and negativity
DEREK does not provide quantitative assessment, but checks
if structural alerts in the knowledge base can be identied in the
query structure. It describes the molecular substructures that have
been associated with the toxicity (toxicophore) supported by literature references. The rules used are not chemical-specic but serve
as broad generalizations with regard to the chemical structure. The
level of condence in the prediction is indicated, from impossible
to certain. When no alert is found, nothing to report is mentioned.
In this study, DEREK was used together with TOPKAT and the
predictions were considered reliable when prediction results were
concordant between these two SARs.
3. Results
3.1. Identication of pyrazines
Identication of target compounds was made by matching MS
spectra and retention times, which are shown in Table 1. MS SIM
chromatograms obtained with non-polar and polar column are
shown in Figs. 1 and 2 respectively.
Best separation was obtained with the polar column that could
separate all the isomers except 2-ethyl-3-methylpyrazine and
2,3,5-trimethylpyrazine but those compounds can be identied by
their spectra. Nevertheless, m/z 42 used for 2,3,5-trimethylpyrazine
was interfered by ethanolamine as shown on the last chromatogram in Fig. 2. Therefore this compound was preferentially
analyzed with the non-polar column. The only doubt remaining
was about the identication of isomers 2-ethyl-5-methylpyrazine

and 2-ethyl-6-methylpyrazine: they were well separated but the

only available standard was a mixture of both isomers. The denitive identication was allowed by a NMR analysis of the standard
mixture.
3.2. Quantication
A semi-quantitative approach was applied to obtain an approximate content of all pyrazines identied in liquid samples from
IFPEN and EDF R&D CO2 capture pilot plants. MS SIM chromatograms were used to evaluate the amount of the target products
as shown in Fig. 3. An external calibration was made with a mix of
the ten pyrazines studied by spiking a solution of water/MEA at
three levels of concentration. The results obtained for liquid samples are reported in Table 2. The pooled relative uncertainty on
the pyrazines amount determination has been roughly estimated
around 18% by using two repetitions obtained in intermediate precision conditions, i.e. column and day different. To be sure that
pyrazines were produced by a degradation process, the water/MEA
mixture originally introduced in the pilot plant was analyzed before
the pilot plant experience was launched. All pyrazines could be
found at traces levels, between 60 times less than in the degraded
sample for 2-ethyl-3-methylpyrazine and 300 times less for 2,3dimethylpyrazine. 10 pyrazines were observed in the case of IFPEN
pilot plant and 7 among them in the case of EDF R&D pilot plant.
This result can be explained by the shorter duration of EDF R&D pilot
plant campaign and therefore the smaller amount of pyrazine alkylation conrmed by a higher concentration of pyrazine in this case.
Pyrazine concentration was compared with some known degradation products to assess its relative abundance in the IFPEN sample:
pyrazine concentration was very close to acetate and oxalate ions
concentrations (55 ppm and 53 ppm, respectively). Nevertheless,
identied pyrazine derivatives are less concentrated in the liquid

Fig. 1. Chromatograms in SIM mode, after HS-SPME, of a mix of 10 pyrazines (pyrazine and 2-methylpyrazine were at 1 mg/L, other alkylpyrazines were at 0.1 mg/L) in a
water/MEA solution with the non-polar column and the associated temperature programme.

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

579

Fig. 2. Chromatograms in SIM mode, after HS-SPME, of a mix of 10 pyrazines (pyrazine and 2-methylpyrazine were at 10 mg/L, other alkylpyrazines were at 0.1 mg/L) in a
water/MEA solution with the polar column and the associated temperature programme.

phase than carboxylic ions but they are more concentrated in the
gas phase because of their much higher volatility. Their presence
in the gas phase is proved by HS-SPME method using a temperature (70 C) close to highest temperatures encountered in absorber
conditions.
3.3. Mechanism of formation
A mechanism for the formation of pyrazine derivatives is proposed in Figs. 4 and 5. Their formation is due to the presence

of 2-aminoacetaldehyde, formaldehyde and acetaldehyde. Oxidation of MEA in 2-aminoacetaldehyde is very easy in pilot plant
conditions (Rooney et al., 1998), and the presence of formaldehyde and acetaldehyde was previously reported by Rooney et al.
(1998) and Sexton and Rochelle (2011). The rst step is a fast
condensation of two 2-aminoacetaldehyde molecules followed by
a dehydration leading to dihydropyrazine. This molecule is then
easily oxidized in pyrazine as explained by Krems and Spoerri
(1947) in a review; this oxidation was also observed by Guerra
and Yaylayan (2010) during a pyrolysis at 150 C and by Adams

Fig. 3. Chromatogram SIM (TIC), after HS-SPME, of a liquid sample from IFPEN CO2 capture pilot plant with the polar column and the associated temperature programme.

580

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

Table 2
Average concentrations of ten alkylpyrazines in liquid samples from IFPEN and EDF
R&D CO2 capture pilot plants.
Pyrazines

Concentrations in
IFPEN pilot plant
sample (mg/L)

Concentrations in
EDF R&D pilot plant
sample (mg/L)

Pyrazine
2-methylpyrazine
2,5-dimethylpyrazine
2,6-dimethylpyrazine
2-ethylpyrazine
2,3-dimethylpyrazine
2-ethyl-6-methylpyrazine
2-ethyl-5-methylpyrazine
2,3,5-trimethylpyrazine
2-ethyl-3-methylpyrazine

50
3
0.02
0.13
0.28
0.20
0.04
Traces
0.01
0.02

100
1
Traces
Traces
Traces
0.03
<LOD*
<LOD*
Traces
<LOD*

reported to naturally occur in foods (Maarse et al., 1999; Maga,

1982; Tang et al., 1983).
These molecules are absorbed, distributed and excreted rapidly
when administered orally to rats (Sjoedin et al., 1989). Acute oral
toxicity effects in rats are summarized in Table 3 (LD50 values
Lethal Dose with 50% of mortality). They indicate a low to moderate level of toxicity with values ranging from 600 to 1800 mg/kg
for seven pyrazine derivatives (Moran et al., 1980). Most of the
predicted LD50 values obtained with TOPKAT correlate well with
the experimental values (excepted for 2-methylpyrazine where
the prediction is lower than the experimental value). Although
no data was available for pyrazine, 2-ethylpyrazine and 2-ethyl6-methylpyrazine, predicted LD50 values obtained with TOPKAT
were provided (706, 959, and 592 mg/kg, respectively). Concerning other acute toxicity endpoints such as skin and eye irritation, or
skin sensitization, no published literature was available. DEREK and
TOPKAT predictions on irritation potency were different. DEREK did
not ag any alert whereas TOPKAT predicted the substances to be
moderate/severe irritant for the eyes and skin. The level of condence for these TOPKAT predictions was considered to be low due
to the poor similarity between substances of the training set and
pyrazine derivatives. However classication for skin irritation and
eye damage were proposed for 2,6-dimethylpyrazine and 2,3,5,6tetramethylpyrazine, and in a lesser extend for 2-methylpyrazine
(skin and eye irritation) in the classication and labelling inventory
(database containing classication on substances notied under
REACH regulation). These proposed classications are based on
experimental results, but the detailed results are not available.
Taken together the data strongly suggests that these substances
are eye and skin irritants.
The genotoxicity potential of pyrazine and pyrazine derivatives has been extensively tested. They were reported negative

*Limit of detection = 0.5 ppb.

et al. (2008) during a reaction at 90 C. Conditions used by Adams

et al. (2008) can be encountered in the case of CO2 capture. On
the other hand dihydropyrazine can react with formaldehyde or
acetaldehyde to form 2-methylpyrazine or 2-ethylpyrazine respectively (Adams et al., 2008; Guerra and Yaylayan, 2010). The formed
alkylpyrazines can give di- or trialkylpyrazines by electrophilic
addition catalyzed by a metal in presence of a base (Bramwell et al.,
1971) as shown in Fig. 5. Thanks to metal, SET (single electron transfer) occurs, therefore alkylpyrazines can react with formaldehyde
to form dialkylpyrazines then trialkylpyrazines.
3.4. Toxicity assessment
Pyrazine and some of its alkyl derivatives were identied in
tobacco smoke as long ago as 1968 (Stedman, 1968) and have been

H2
N

H
N

OH

N
[O]

- 2 H2O

x2

OH [O]

H2N

H
N

aromatisation
H2N

N
H2

HO

N
H

N
H

pyrazine

R
OH
N

N
H

- H+

R= H, CH3
N

-H2O

Fig. 4. Mechanism of pyrazine and alkylpyrazines formation.

Adapted from Krems and Spoerri (1947), Adams et al. (2008), and Guerra and Yaylayan (2010).

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

581

O
N

N
R

metal

N
R

proton
transfer

SET
N

N
O

R = H or CH3

- OH-

OH

N
R

+H
N

N
Fig. 5. Mechanism of pyrazine alkylation.
Adapted from Bramwell et al. (1971).

Table 3
Oral acute toxicity of pyrazine derivatives.
Substance

Oral LD50 mg/kg bw (rat)

2-methylpyrazine
2,3-dimethylpyrazine
2,5-dimethylpyrazine
2,6-dimethylpyrazine
2-ethyl-3-methylpyrazine
2-ethyl-5-methylpyrazine
2,3,5-trimethylpyrazine
Pyrazine
2-ethylpyrazine
2-ethyl-6-methylpyrazine

1800
613
1020
880
600
900
806
ND
ND
ND

TOPKAT prediction

Study reference

Outside OPS (score)

Rat oral LD50 mg/kg bw

No
No
No
No
No
No
No
No
No
No

947
903
1049
738
526
779
1002
706
959
592

(Beckman et al., 2011;

Moran et al., 1980)

ND: No data.

in mutation tests conducted in bacteria (Ames tests) (Stich et al.,

1980). Experimental data was available on a large number of
pyrazine derivatives including 7 molecules on the list of interest
(Table 4). In the study of Stich et al. (1980), 2-methylpyrazine,
2-ethylpyrazine, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, and
pyrazine were shown to induce chromosome aberrations in Chinese Hamster Ovary (CHO) cells and to increase the mutation
frequency in yeast (Saccharomyces cerevisiae D5). However, the
increase in chromosome aberrations was found in a single report
conducted with high toxic concentrations, which could have led to

unspecic chromosome damage. Furthermore, pyrazine was negative in a gene mutation test conducted in mouse lymphoma cells
(Mouse Lymphoma TK assay) (Fung et al., 1988) indicating no mutagenic or clastogenic activity of pyrazine. According to DEREK and
TOPKAT predictions, no structural alert for mutagenic or clastogenic potential was identied among the ten molecules except
for 2,6-dimethylpyrazine, which showed conicting predictions
for mutagenicity in bacteria (positive with TOPKAT and negative
with DEREK). Taken together, these observations suggest that positive responses obtained by Stich et al. should be considered as

Table 4
Genotoxicity studies and computational predictions.
Substance

Pyrazine
2-methylpyrazine
2,5-dimethylpyrazine
2,6-dimethylpyrazine
2,3-dimethylpyrazine
2-ethylpyrazine
2,3,5-trimethylpyrazine
2-ethyl-3-methylpyrazine
2-ethyl-5-methylpyrazine
2-ethyl-6-methylpyrazine

AMES
studiesa,b,c,d

N
N
N
N/P
N
N
N
ND
ND
ND

N, negative; P, positive; ND, no data.

a
Stich et al. (1980).
b
Aeschbacher et al. (1989).
c
Lee et al. (1994).
d
Fung et al. (1988).
e
Discordant predictions.

Mutation assay
S. cerevisiaea

P
P
P
P
ND
P
ND
ND
ND
ND

Chromosome
aberration studiesa

P
P
P
P
ND
P
ND
ND
ND
ND

TOPKAT
prediction

DEREK prediction

AMES

AMES

Chromosome
damage (in vitro)

Chromosome
damage (in vivo)

N (0.720)
N (0.654)
N (0.694)
P (0.739)e
N (0.685)
N (0.535)
N (0.681)
N (0.687)
N (0.622)
N (0.661)

N
N
N
Ne
N
N
N
N
N
N

N
N
N
Ne
N
N
N
N
N
N

N
N
N
Ne
N
N
N
N
N
N

582

A. Rey et al. / International Journal of Greenhouse Gas Control 19 (2013) 576583

non-relevant for either classication or human risk assessment and

that the identied pyrazines derivatives did not show genotoxic
potential.
Concerning the sub-chronic toxicity of pyrazine derivatives, information on repeated dietary exposure was obtained
on 2-ethyl-3-methylpyrazine, 2-ethyl-5-methylpyrazine or 2,3,5trimethylpyrazine. In these studies rats were exposed to 5, 18 and
18 mg/kg body weight (bw)/day of the corresponding pyrazines for
ninety days. No adverse effects were reported in these studies and
therefore the No Observed Adverse Effect Levels (NOAELs) were set
at 5 or 18 mg/kg bw/day, respectively (Oser et al., 1965; Posternak
et al., 1969). No studies are available on chronic toxicity or on
carcinogenicity with either pyrazine or the pyrazine derivatives
identied in this study.
The effects of three dimethylpyrazine isomers were studied for
effects on the reproductive organs of male and female rats after subcutaneous injection. The route of exposure is not relevant to human
exposure but the effects were reported in order to highlight some
potential adverse effects that would need further investigations.
The 2,5-dimethylpyrazine was shown to decrease uterus weight
in female rats at 100 mg/kg/day (Yamada et al., 1992). In males
exposed to 2,5-dimethylpyrazine, decreases in plasma testosterone
level, in prostate and seminal vesicle weights were reported at
70 mg/kg/day in juvenile but not in mature animals and these
effects were no longer observed at 30 mg/kg/day (Yamada et al.,
1994). At 100 mg/kg/day the 2,6-dimethylpyrazine only showed
effects on seminal vesicles and no effects were reported with 2,3dimethylpyrazine (Yamada et al., 1993). Therefore, a NOAEL for
reproductive toxicity was established at 30 mg/kg bw/day based on
the adverse effects of 2,5-dimethylpyrazine in juvenile male rats.
Based on their low aroma threshold and on their rapid absorption, metabolism, and excretion in humans, pyrazine derivatives
were considered as safe (GRAS) by FEMA (Renberg et al., 1989).
Based on the MSDI approach the estimated level of intake ranged
from 0.2 to 120 g/day in Europe (JEFCA, 2002; with estimated
intake of 0.2 g/person per day for pyrazine and 120 g/person
per day for trimethylpyrazine). Therefore, at the level of European
dietary intake and according to the data provided in this study
(published literature, in silico predictions and classications issued
from inventory data bases) the identied pyrazines are currently
not indicating toxicological concerns.
4. Conclusion
Although MEA is the most studied amine, ten new degradation
products were found in this work: pyrazine and nine alkyl derivatives. To do that a new analytical method based on HS-SPME and
GCMS was developed.
Pyrazines were quantied and a mechanism was proposed for
their formation in accordance with literature.
Then their toxicity was assessed. Available toxicological data
were used and, when information was not sufcient, a computational approach was conducted. Predictions were generated by
using two SARs (structureactivity relationship) software tools:
TOPKAT and DEREK.
The study showed that the ten identied pyrazines are currently
not indicating toxicological concern at the level of intake estimated
at 0.2120 g/day in Europe.
Acknowledgments
The authors would like to acknowledge nancial support from
French ANR (Research Project DALMATIEN).
This work is a part of the PhD thesis of C. Gouedard supported
by IFPEN and hosted by MATIS LABEX.

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